Method for producing 8-methoxy-quinoline carboxylic acids

ABSTRACT

The present invention relates to a novel process for preparing 8-methoxy-3-quinolonecarboxylic acids which are antibiotics having potent antibacterial action.

[0001] The invention relates to a process for preparing8-methoxy-quinolonecarboxylic acids.

[0002] 8-Methoxy-quinolonecarboxylic acids are antibiotics having potentantibacterial action against Gram-negative and Gram-positive bacteria.Thus, for example, the antibiotics1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid (INN: gatifloxacin, EP-A-230 295) and1-cyclopropyl-7-[S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolonecarboxylicacid hydrochloride monohydrate (Bay 12-8039, EP-A-0 350 733) have amethoxy group in the 8-position.

[0003] Such highly potent antibacterial quinolonecarboxylic acidsusually have a heteromonocyclic or heteropolycyclic amine radical in the7-position of the quinolonecarboxylic acid. This cyclic amine radical isgenerally prepared by nucleophilic substitution of the corresponding7-halogeno-quinolonecarboxylic acid with the respective amine. Inprinciple, the 8-alkoxy group can be introduced before the introductionof the cyclic amine radical in the 7-position, or afterwards. Thus,EP-A-0 350 733 describes the preparation of the racemic betaine of theabovementioned Bay 12-8039, starting from the corresponding 8-methoxycompound whose preparation is described in EP-A-0 241 206 (Preparation6), by nucleophilic substitution with the corresponding racemic amine.Analogously, the preparation of the enantiomerically pure betaine of Bay12-8039 starting from the 8-methoxy compound by nucleophilicsubstitution with the enantiomerically pure amine is described in EP-A-0550 903 (Example 19). However, the synthesis route described thereinrequires complicated isolation and purification by column chromatographywhich is undesirable for industrial scale. The latter approach is alsoused in EP-A-0 591 808 (Example Z 19).

[0004] Another way of introducing an 8-alkoxy substituent into the7-amine-substituted quinolonecarboxylic acids consists in 8-alkoxysubstitution after the cyclic amine substituent has been introduced intothe 7-position of the corresponding 7,8-dihalogeno starting material.

[0005] Thus, EP-A-0 106 489 describes the route of 8-methoxysubstitution after introduction of the heterocyclyl substituent in the7-position by reaction of the corresponding 8-fluoro compound inmethanol in the presence of potassium tertbutoxide. However, thereaction which is carried out in this publication with the7-[2-[(methylamino)-methyl]-4-thiazole] compound requires 24 hours underreflux and is therefore unsuitable for a reaction on an industrialscale. Furthermore, it was observed that certain quinolonecarboxylicacids, such as, for example, the Bay 12-8039 described above, can not beprepared by this route since no reaction takes place under theconditions of the conversion under reflux for 24 hours.

[0006] EP-A-02 30 295 likewise describes the route of 8-alkoxysubstitution starting from 8-halogeno-7-monocycloamine derivatives inmethanol in the presence of alkali metal alkoxides. However, thereaction in the presence of sodium methoxide described in the examplesof this publication requires very high temperatures of approximately 140to 150° C. and very long reaction times, and the reaction is carried outin closed vessels under pressure. However, this process is not generallyapplicable for preparing 8-methoxy-quinolonecarboxylic acids. Thus,application of this process for preparing the above-described Bay12-8039 does not lead to formation of end product even after 70 hours ifthe solvent used is MeOH.

[0007] If the reaction of the corresponding 8-fluoro compound withsodium methoxide is carried out in tetrahydrofuran, complete conversionrequires very long reaction times (>24 h) and a large excess ofmethoxide.

[0008] In a similar manner, preparation of the 8-alkoxy derivatives inEP-A-0 235 762 is carried out by reacting the8-halogeno-7-monocycloaniine derivatives with alkali metal alkoxides.Furthermore, the preparation of 8-methoxy-quinolonecarboxylic acids byreacting the alkali metal alkoxides in solvents such as DMI (WO93/22308, Chugai), with sodium methoxide in DMF or DMSO (EP-A-0 342 675,Chugai), with benzyl alcohol/sodium hydride (Research Disclosure No. 291097, 1988), with sodium methoxide in DMF at 80° C. for 9 hours (JP03007283 Yoshitomi), with methanol and a base (WO 90/06305, Dainippon),with NaH/trifluoroethanol in DMF (WO 92/09579), with sodium methoxide inmethanol (JP-62 252772), with sodium methoxide/DMI at 80° C. (JP-05117238, Chugai) and the reaction with sodium methoxide in methanol (J. Med.Chem. 30, 2163-2169) is described.

[0009] It is true that the reaction of the 8-halogen compounds withalkali metal alkoxides in polar aprotic solvents such as, for example,DMF generally leads to a virtually complete conversion if the alkalimetal alkoxide is employed in excess. However, isolation of salts of the8-alkoxy-quinolonecarboxylic acids from such solvents is complicated andvirtually impossible to realize on an industrial scale.

[0010] It is therefore an object of the present invention to develop aprocess for preparing 8-methoxy derivatives of quinolonecarboxylic acidswhich permits short reaction times, operation under atmosphericpressure, complete conversion and easy work-up of the reaction mixture.

[0011] Surprisingly, it is possible to obtain8-methoxy-quinolonecarboxylic acid derivatives in a process which meetsthe above conditions, by reacting the corresponding8-halogeno-quinolonecarboxylic acid derivatives with (C₁-C₃)-alkanols orbenzyl alcohol and sodium tert-butoxide or potassium tert-butoxide orsodium tert-amylate or potassium tert-amylate in the presence ofaliphatic or cycloaliphatic ethers having 4 to 6 carbon atoms assolvent.

[0012] The invention, accordingly, provides a process for preparingcompounds of the formula

[0013] in which

[0014] R′ and R″ together with the linking nitrogen atom form a mono- orbicyclic heterocycle which may optionally contain in all ring moietiesfurther nitrogen, oxygen or sulphur heteroatoms and which may optionallybe substituted,

[0015] in which

[0016] R¹ represents C₁-C₃-alkyl, FCH₂—CH₂—, cyclopropyl, or representsphenyl or cyclopropyl, each of which is optionally mono- totrisubstituted by halogen,

[0017] R² represents C₁-C₃-alkylorbenzyl,

[0018] R³ represents H, halogen, NH₂, CH₃,

[0019] characterized in that 8-halogeno-3-quinolonecarboxylic acidderivatives of the general formula

[0020] in which

[0021] Hal represents fluorine or chlorine and

[0022] R¹, R², R³ and

[0023]  are each as defined above,

[0024] are reacted in an aliphatic or cycloaliphatic ether having 4 to 6carbon atoms as solvent in the presence of C₁-C₃-alkanols or benzylalcohol with

[0025] in which

[0026] M represents sodium or potassium.

[0027] The group

[0028] forms a mono- or bicyclic heterocycle which may optionallycontain in all ring moieties further nitrogen, oxygen or sulphurhetero-atoms and which may optionally be substituted. The ring membersR′ and R″ may represent identical or different ring components. Suchmono- or bicyclic amine radicals in the 7-position of thequinolonecarboxylic acid skeleton are known in principle in the field ofthe quinolonecarboxylic acid antibiotics. By way of example, the patentpublications EP-A-0 523 512, EP-A-0 230 295, EP-A-0 705 828, EP-A-0 589318, EP-A-0 357 047, EP-A-0 588 166, GB-A-2 289 674, MIO 92/09 579,JP-03-007 283, EP-A-0 241 206, EP-A-0 342 675, WO 93/22 308 and EP-A-0350 733 may be mentioned.

[0029] Among these known amine radicals,

[0030] preferably represents

[0031] Very particularly preferably,

[0032] represents

[0033] in which

[0034] T represents —O— or —CH₂— and

[0035] R⁴ represents hydrogen, C₁-C₃-alkyl, C₂-C₅-oxoalkyl,—CH₂—CO—C₆H₅, —CH₂CH₂CO₂R⁵,

[0036]  5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, —CH═CH—CO₂R⁵ or—CH₂CH₂—CN,

[0037] in which

[0038] R⁵ represents hydrogen or C₁-C₃-alkyl,

[0039] and the formula (a) includes any mixtures of the stereoisomers(b) to (e).

[0040] The amines corresponding to these definitions of

[0041] are described in EP-A-0 550 903, and their reaction with thecorresponding 6,7,8-trihalogeno-quinolonecarboxylic acids leads to thestarting materials of the process according to the invention.

[0042] The aliphatic or cycloaliphatic ether having 4 to 6 carbon atomsis preferably selected from the group consisting of dimethoxyethane,dioxane and tetrahydrofuran.

[0043] Particularly high yields and short reaction times are achievedusing tetrahydrofuran.

[0044] In the process according to the invention, Hal preferablyrepresents fluorine.

[0045] The (C₁-C₃)-alkanol is preferably methanol, i.e. the process ispreferably used for preparing the 8-methoxy compound.

[0046] M is preferably potassium, i.e. the reaction is preferablycarried out using potassium tert-butoxide or potassium tert-amylate,particularly preferably using potassium tert-butoxide.

[0047] Based on 1 equivalent of the compound of the formula

[0048] preferably 1 to 3, particularly preferably 1.1 to 1.3,equivalents of the (C₁-C₃)-alkanol or the benzyl alcohol, and 2 to 3,preferably 2.1 to 2.3, equivalents of the compound of the formula

[0049] are employed.

[0050] The reaction is preferably carried out between 20° C. and theboiling point of the solvent at atmospheric pressure.

[0051] The process of the present invention is particularly suitable forpreparing compounds of the formula

[0052] in which

[0053] R² represents C₁-C₃-alkyl or benzyl.

[0054] Here,

[0055] is preferably reacted in an aliphatic or cycloaliphatic etherhaving 4 to 6 carbon atoms as solvent in the presence of C₁-C₃-alcoholsor benzyl alcohol with

[0056] in which

[0057] M represents sodium or potassium.

[0058] The process is preferably carried out in dimethoxyethane,dioxane, tetrahydrofuran or mixtures of these.

[0059] Particularly preferably, the process is carried out intetrahydrofuran as solvent.

[0060] The (C₁-C₃)-alkanol is preferably methanol, i.e. the 8-methoxycompound is prepared (Bay 12-8039).

[0061] M is preferably potassium.

[0062] Based on 1 equivalent of the compound of the formula

[0063] preferably 1 to 3, particularly preferably 1.1 to 1.3,equivalents of the (C₁-C₃)-alkanol or the benzyl alcohol, and 2 to 3,preferably 2.1 to 2.3, equivalents of the compound of the formula

[0064] are employed.

[0065] The process is preferably carried out between 20° C. and theboiling point of the solvent at atmospheric pressure.

[0066] The process of the present invention is particularly suitable forpreparing

[0067] is reacted with methanol and preferably potassium tert-butoxidein tetrahydrofuran as solvent.

[0068] Based on one equivalent of the compound of the formula

[0069] preferably 1 to 3, particularly preferably 1.1 to 1.3,equivalents of methanol and 2 to 3, preferably 2.1 to 2.3, equivalentsof potassium tert-butoxide are employed, and the reaction is carried outbetween 20° C. and the boiling point of the solvent at atmosphericpressure.

[0070] A particular advantage of the process according to the inventionconsists in the fact that preparation of pharmaceutically acceptablesalts, for example the hydrochlorides, of the above-described compoundssucceeds in a particularly simple manner by admixing the resultingreaction mixture with dilute hydrochloric acid or by adding the reactionmixture to dilute hydrochloric acid and isolating the salt, preferablythe hydrochloride, by filtration. This immediate preparation of thehydrochloride is preferably employed for preparing the compound of thefollowing formula:

[0071] In a further aspect of the present invention, the compounddescribed above (Bay 12-8039, hydrochloride) can surprisingly beisolated in high purity by recrystallization from water or awater/(C₁-C₃)-alkanol mixture. The purity of the compound obtained inthis manner is already sufficient for many pharmaceutical applications.The recrystallization is preferably carried out from water or awater/ethanol mixture.

[0072] From the hydrochloride described above, it is furthermoresurprisingly possible to obtain in a simple manner on industrial scale aparticularly stable monohydrate of the formula

[0073] having a particular crystal structure, as described in DE-A-1 9546 249 (corresponds to EP-A-0 780 390), by drying the resulting productat from 40 to 60° C. and from 80 to 120 mbar. This drying isparticularly preferably carried out at approximately 50° C. andapproximately 100 mbar.

[0074] In the above definitions, (C₁-C₃)-alkyl or -alkyl radicalsgenerally represent, for example, methyl, ethyl, propyl, isopropyl.

[0075] Particularly preferably, (C₁-C₃)-alkyl and the (C₁-C₃)-alkylradical in the corresponding aliphatic radicals represents methyl.

EXAMPLE 1

[0076] Preparation of1-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0)non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolonecarboxylicAcid Hydrochloride Using Potassium tert-butoxide

[0077] Quantities Employed: 50.0 g (0.129 mol)1-Cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6,8-difluoro-1,4-dihydroxy-4-oxo-3- quinolonecarboxylic acid (Bay z 7906) (preparedaccording to Example 1 of EP-A-0 550 903). 270.0 ml THF 6.2 ml (0.155mol) Methanol 159.1 g (0.284 mol) Potassium tert-butoxide solution (20%strength in THF) 128 ml Water 38 ml Hydrochloric acid, conc. 30 ml Water60 ml Ethanol 110 ml Ethanol 330 ml Water 3 × 15 ml Ethanol

[0078] Procedure:

[0079] Under nitrogen, 50.0 g of Bay z 7906 in 270 ml of THF and 6.2 mlof methanol were initially charged in a 1000 ml three-necked flaskfitted with stirrer and thermometer. The mixture is heated and, fromapproximately 60° C. onwards. 80 ml of a potassium tert-butoxidesolution (20% strength in THF), corresponding to 1 equivalent, is addedover a period of approximately 5 min. A yellow suspension results, whichslowly becomes more viscose and which is finally white. The mixture isstirred under reflux for 15 min. The suspension does not change. Underreflux, the remaining potassium tert-butoxide solution is added over aperiod of 5 min. The mixture is stirred at reflux for 2.5 hours andsubsequently cooled to room temperature.

[0080] To precipitate the hydrochloride, 128 ml of water and 38 ml ofconc. hydrochloric acid are initially charged in a double-jacket flaskfitted with stirrer, revolution counter and thermostat. With cooling andat 500 rpm, the reaction solution obtained above is added dropwise overa period of 2 hours at approximately 20 to 22° C. After the addition ofapproximately 50 ml, the mixture is seeded with-12.5 mg of Bay 12-8039.After the addition is complete, the mixture is stirred at 8° C. forapproximately 30 min. A solution forms. The mixture is filtered and thefilter cake is washed first with 30 ml of water and then with 60 ml ofethanol. The precipitated end product can be filtered very easily and isdried at 50° C. under reduced pressure.

[0081] This gives 47.1 g of the product.

[0082] Purification and Monohydrate Formation

[0083] For purification, 46.6 g of the precipitated product aredissolved under reflux in 110 ml of ethanol/330 ml of water, and themixture is allowed to cool to 20 to 22° C. over a period of 2 hours. Atapproximately 50° C., the mixture is seeded with 12.5 mg of Bay 12-8039.The seed crystals do not dissolve. The mixture is stirred at 20 to 22°C. for a further hour and filtered, and the filter cake is washed with3×15 ml of ethanol. Drying at approximately 50° C. and a pressure of 100mbar results in the defined formation of the monohydrate of Bay 12-8039hydrochloride.

[0084] This gives 31.9 g of yellow crystals of a purity which issufficient for many pharmacological applications.

EXAMPLE 2

[0085] Preparation of1-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0)non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolonecarboxylicAcid Hydrochloride Using Potassium tert-amylate

[0086] Quantities Employed: 10.0 g (25.7 mmol) Bay z 7906, Pt. 501781 54ml THF 1.24 ml (30, 8 mmol) Methanol 35.6 g (56, 5 mmol) Potassiumtert-amylate solution (20% strength in THF) 26.6 ml Water 7.6 mlHydrochloric acid, conc. 6.0 ml Water 12.0 ml Ethanol

[0087] Procedure:

[0088] 10 g of Bay z 7906 are initially charged in 54 ml of THF and 1.24ml of methanol. The mixture is heated, and 17 ml of potassiumtert-amylate solution (20% strength in THF), corresponding to 1equivalent, are added from 60° C. onwards over a period of approximately5 minutes. The mixture is then stirred under reflux for 30 minutes.Under reflux, the remaining potassium tert-amylate solution is addedover a period of 5 minutes. The mixture is stirred at reflux for 2.5hours and subsequently cooled to room temperature. To precipitate thehydrochloride, 26.6 ml of water and 7.6 ml of hydrochloric acid (conc.)are initially charged. At 500 rpm and with cooling, the reactionsolution is added dropwise over a period of 2 hours at approximately 20to 22° C. After addition of approximately 9 ml, the mixture is seededwith Bay 12-8039. After the addition is complete, the mixture is stirredat 8° C. for 30 minutes. A suspension is formed. The suspension isfiltered and the filter cake is washed first with 6 ml of water and thenwith 12 ml of ethanol and dried under reduced pressure at 50° C. Thisgives 8.6 g.

[0089] The product can be purified and converted into the monohydrateusing the procedure of Example 1.

COMPARATIVE EXAMPLE

[0090] (Reaction of Bay z 7906 in THF with Sodium Methoxide)

[0091] Amounts Employed: 50.0 g (0.129 mol) Bay z 7906 1040 ml THF 116.1g (0.645 mol) Sodium methoxide solution (30% strength in methanol) 49 mlHydrochloric acid, conc. 77 ml THF 38 ml Water 385 ml Water 2 × 38 mlWater 297 ml Methanol 2 × 10 ml Methanol 68 ml Ethanol 34 ml Water 2 ×10 ml Ethanol

[0092] Procedure:

[0093] In a 2000 ml three-necked flask fitted with stirrer andthermometer, 50.0 g of Bay z 7906 in 1040 ml of THF and 116.1 g ofsodium methoxide solution (30% strength in methanol) are initiallycharged under nitrogen. With stirring, the mixture is heated to refluxand the progress of the reaction is monitored by HPLC.

[0094] (Bay z 7906 [Starting Material] Content:

[0095] after 6 h RF=56.5%;

[0096] after 30 h RF=11.7%;

[0097] after 70 h RF=1.4%).

[0098] After 70 hours of stirring under reflux, the mixture is cooled to10 to 15° C. and adjusted to pH 6.8 to. 7.0 using conc. hydrochloricacid (consumption of conc. hydrochloric acid 48 ml). The precipitate isfiltered off with suction and washed first with 77 ml of THF and thenwith 38 ml of water.

[0099] The moist solid (108.2 g) is suspended in 3g5 ml of water,stirred at 20 to 25° C. for 30 minutes, filtered off with suction andwashed twice with 38 ml of water (poor filtration properties).

[0100] The solid is dried under reduced pressure at 50° C. (40.4 g) anddissolved at reflux in 297 ml of methanol.

[0101] After cooling to approximately 10° C., the precipitated crystalsare filtered off with suction and washed twice with 10 ml of methanoleach time.

[0102] The solid is dried under reduced pressure at 50° C. (21.1 g) anddissolved under reflux in 68 ml of ethanol and 34 ml of water. Aftercooling to 20 to 25° C., the mixture is stirred for one hour and theprecipitated crystals are filtered off with suction and washed twicewith 10 ml of ethanol. Drying under reduced pressure at 50° C. gives16.2 g of orange crystals.

[0103] Comparison between the examples according to the invention andthe comparative example shows that, even after a reaction time of 70 h,the reaction with sodium methoxide in THF gives a lower yield.

[0104] The process according to the invention thus offers, in particularon an industrial scale, enormous advantages in terms of yield, reactiontime and work-up.

1. Process for preparing 3-quinolonecarboxylic acid derivatives of the general formula

in which R′ and R″ together with the linking nitrogen atom form a mono- or bicyclic heterocycle which may optionally contain in all ring moieties further nitrogen, oxygen or sulphur heteroatoms and which may optionally be substituted, in which R¹ represents C₁-C₃-alkyl. FCH₂—CH₂—, cyclopropyl, or represents phenyl or cyclopropyl, each of which is optionally mono- to trisubstituted by halogen, R² represents C₁-C₃-alkyl or benzyl, R³ represents H, halogen, NH₂, CH₃, characterized in that 8-halgeno-3-quinolonecarboxylic acid derivatives of the general formula

in which Hal represents fluorine or chlorine and R¹, R², R³ and

 are each as defined above, are reacted in an aliphatic or cycloaliphatic ether having 4 to 6 carbon atoms as solvent in the presence of C₁-C₃-alkanols or benzyl alcohol with

M represents sodium or potassium.
 2. Process according to claim 1, characterized in that the solvent is selected from the group consisting of dimethoxyethane, dioxane and tetrahydrofuran.
 3. Process according to claim 2, characterized in that the solvent is tetrahydrofuran.
 4. Process according to any of claims 1 to 3, characterized in that Hal represents fluorine.
 5. Process according to any of claims 1 to 4, characterized in that the (C₁-C₃)-alkanol is methanol.
 6. Process according to any of claims 1 to 5, characterized in that M is potassium.
 7. Process according to any of claims 1 to 6, characterized in that based on 1 equivalent of the compound of the formula

1 to 3, preferably 1.1 to 1.3, equivalents of the (C₁-C₃)-alkanol or the benzyl alcohol, and 2 to 3, preferably 2.1 to 2.3, equivalents of the compound of the formula

are employed.
 8. Process according to any of claims 1 to 7, characterized in that the reaction is carried out between 20° C. and the boiling point of the solvent at atmospheric pressure.
 9. Process for preparing 3-quinolonecarboxylic acid derivatives according to any of claims 1 to 8 in which


10. Process for preparing 3-quinolonecarboxylic acid derivatives according to any of claims 1 to 8 in which

in which T represents —O— or —CH₂— and R⁴ represents hydrogen, C₁-C₃-alkyl, C₂-C₅-oxoalkyl, —CH₂—CO—C₆H₅, —CH₂CH₂CO₂R⁵,

 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, —CH═CH—CO₂R⁵ or —CH₂CH₂—CN, in which R⁵ represents hydrogen or C₁-C₃-alkyl, and the formula (a) includes any mixtures of the stereoisomers (b) to (e).
 11. Process for preparing

in which R² represents C₁-C₃-alkyl or benzyl, characterized in that

is reacted in an aliphatic or cycloaliphatic ether having 4 to 6 carbon atoms as solvent in the presence of C₁-C₃-alcohols or benzyl alcohol with

in which M represents sodium or potassium.
 12. Process according to claim 11, characterized in that the solvent is selected from the group consisting of dimethoxyethane, dioxane and tetrahydrofuran.
 13. Process according to claim 11, characterized in that the solvent is tetrahydrofuran.
 14. Process according to claim 11, characterized in that the (C₁-C₃)-alkanol is methanol.
 15. Process according to claim 11, characterized in that M is potassium.
 16. Process according to claim 11, characterized in that based on 1 equivalent of the compound of the formula

1 to 3, preferably 1.1 to 1.3, equivalents of the (C₁-C₃)-alkanol or the benzyl alcohol, and 2 to 3, preferably 2.1 to 2.3, equivalents of the compound of the formula

are employed.
 17. Process according to claim 11, characterized in that the reaction is carried out between 20° C. and the boiling point of the solvent at atmospheric pressure.
 18. Process according to claim 11 for preparing

characterized in that

is reacted with methanol and potassium tert-butoxide in tetrahydrofuran as solvent.
 19. Process according to claim 18, characterized in that based on one equivalent of the compound of the formula

1 to 3, preferably 1.1 to 1.3, equivalents of methanol and 2 to 3, preferably 2.1 to 2.3, equivalents of potassium tert-butoxide are employed.
 20. Process according to any of claims 18 or 19, characterized in that the reaction is carried out between 20° C. and the boiling point of the solvent at atmospheric pressure.
 21. Process for preparing

according to any of claims 18 to 20, characterized in that after the reaction the reaction mixture is admixed with dilute hydrochloric acid or the reaction mixture is added to dilute hydrochloric acid and the precipitated hydrochloride is isolated by filtration.
 22. Process for purifying the

obtained, for example, according to claim 21, by recrystillization from water or a water/C₁-C₃-alkanol mixture.
 23. Process according to claim 22, where the recrystillization is carried out from water or a water/ethanol mixture.
 24. Process for preparing

where the product obtained according to claim 22 or claim 23 is dried at from 40 to 60° C. and from 80 to 120 mbar.
 25. Process according to claim 24 where drying is carried out at approximately 50° C. and approximately 100 mbar. 